This Report involves work collected under protocols 01-M-0254 (NCT00024635 ); 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 07-M-0021 (NCT00397111); 14-M-0041 (NCT02049385); and 07-M-0152 (NCT00472576), 09-M-N230; 15-M-0151 (NCT 02484456), 15-M-0188 (NCT02543983). Results this past year: 1. cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor antidepressant. Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using 11C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). We found in unmedicated MDD patients widespread, 20% reductions in 11C-(R)-rolipram binding compared with controls. SSRI treatment significantly increased rolipram binding, with significantly greater increases observed in older patients. Consistent with the results of basic studies, PDE4 was decreased in unmedicated MDD patients and increased after SSRI treatment. These results suggest that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effect. 2. Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder. Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness 3. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis and left rostral middle frontal cortex. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD. 4. Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder: A 3-T 1H-MRS Study. Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using proton magnetic resonance spectroscopy (H-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. Subjects with BD depression showed a significantly higher cingulate cortex (CC) lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline. CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. 5. Active suicidal ideation during clinical antidepressant trials. Suicidal patients are often excluded from clinical trials of psychiatric medications and from investigations using neurobiological techniques. To evaluate the presence, impact, and stability of active suicidal ideation (SI) across a range of antidepressant trials, we reviewed clinical trials conducted in patients with either major depressive disorder (MDD) or bipolar disorder (BD). Across clinical trials, participants (23%) reported active SI at some point during study participation. The results suggest that research can be conducted in depressed patients with active SI if such research coincides with careful observation. Active SI and pessimism may be particularly vulnerable to fluctuation. 6. Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials. Anhedonia occurs across psychiatric diagnoses and has been associated with specific neural circuits in response to rapid-acting treatments, such as ketamine. This analysis included treatment-resistant patients with depression from several clinical trials of ketamine. Anhedonia was assessed using a subscale of the Beck Depression Inventory (BDI) and the Snaith-Hamilton Pleasure Scale (SHAPS). One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. Suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. 7. Acute risk factors for suicide attempts and death: prospective findings from the STEP-BD study. Suicide is unfortunately common in psychiatric practice, but difficult to predict. The present study sought to assess which clinical symptoms increase in the months before suicidal behavior in a sample of psychiatric outpatients with bipolar disorder. Participants were assessed using for the following potential acute risk factors for suicidal behavior: suicidal ideation, loss of interest, anxiety, psychomotor agitation, and high-risk behavior. Each of the five symptoms was elevated overall in individuals who engaged in suicidal behavior. Suicidal ideation, loss of interest and, to a lesser extent, anxiety may represent acute suicide risk factors up to four months before suicidal behavior in outpatients with bipolar disorder. 8. Increased activity or energy as a primary criterion for the diagnosis of bipolar mania in DSM-5. DSM-5 describes a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy as a primary criterion for mania. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder study, the authors analyzed point prevalence data obtained at the initial visit to assess the diagnostic validity of this new DSM-5 criterion. When the new DSM-5 criterion of increased activity or energy was added as a coprimary symptom, the prevalence of mania and hypomania was reduced. The findings confirm that including increased activity or energy as part of DSM-5 criterion A decreases the prevalence of manic and hypomanic episodes but does not affect longitudinal clinical outcomes.